DESCRIPTION (Investigator's Abstract): Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by progressive cognitive impairment, emotional disturbances and a movement disorder. The fundamental biochemical defect underlying neuronal degeneration remains unknown, and there is no known effective therapy. We hypothesis that a defect in energy metabolism could lead to slow excitotoxic neuronal cell death. To eaamine this possibility we have utilized 1H magnetic resonance spectroscopy to determine levels of lactate as well as other neurochemicals in ND patients. In known mitochondrial disorders lactate is elevated in brain and spinal fluid. Our preliminary studies show increased levels of lactate in several brain regions in ND which correlate with the duration of disease. Our most exciting finding is the observation that treatment with coenzyme Q10, which improves mitochondrial function, significantly decreased lactate concentrations in Il of 14 treated patients. This raises the possibility that this might be a useful therapeutic strategy- in HD. The present proposal is to extend these studies. Our first specific aim is to continue to perform IN MRS to determine the regional distribution of changes in lactatc, nacetyl aspartate, creatine and choline in. HD patients as compared with normal controls. We will also carry out studies with 31P- MRS in muscle determine whether an energetic defect could be generalized in HD. Our second specific aim will be to determine if regional elevations of lactate measured by 1H-MRS or CSF lactate/pyrvvate ratios, correlate with duration of symptoms, degree of clinical neurologic impairment, ratings on standard disability scales, age of onset and bradykinetic or choreic phenotype. We will also determine if medications commonly used by HD patients have effects on lactate levels measured by 1N-MRS. Our third specific aim is to determine whether physiologic stimulation of brain regions in ND patients using photic stimulation, or sequential motor tasks result in changes in lactate or magnetic susceptibility which differ from those which occur in normal subjects.Our preliminary findings indicate that photic stimulation results in decreased lactate in occipital cortex, rather than the increases seen in normal subjects. Our last specific aim to use 1H NMS to screen for compounds which lower brain lactate in ND patients and which therefore might be attractive candidates for therapeutic trials. We will continue examining coenzyme Qio and will also examine the effects of riboflavin with nicotinamide and L-carnitine. We will also examine the effects of excitatory amino acid antagonists when these become clinically available. Our preliminary studies provide the first evidence of a possible therapy to treat the underlying disease process in ND. The present proposal has the potential of helping to elucidate the filndaniental biochemical defect underlying ND, and may lead to the development of effective the-for this disorder.